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Below is a press release from the National Institutes of Health (NIH) in the U.S.. on recently published studies on autism risk. These are the studies mentioned by NIMH Director and IACC chair Thomas Insel in his article “The New Genetics of Autism – Why Environment Matters“.

Researchers have turned up a new clue to the workings of a possible environmental factor in autism spectrum disorders (ASDs): fathers were four times more likely than mothers to transmit tiny, spontaneous mutations to their children with the disorders. Moreover, the number of such transmitted genetic glitches increased with paternal age. The discovery may help to explain earlier evidence linking autism risk to older fathers.

The results are among several from a trio of new studies, supported in part by the National Institutes of Health, finding that such sequence changes in parts of genes that code for proteins play a significant role in ASDs. One of the studies determined that having such glitches boosts a child’s risk of developing autism five to 20 fold.

Taken together, the three studies represent the largest effort of its kind, drawing upon samples from 549 families to maximize statistical power. They reveal sporadic mutations widely distributed across the genome, sometimes conferring risk and sometimes not. While the changes identified don’t account for most cases of illness, they are providing clues to the biology of what are likely multiple syndromes along the autism spectrum.

“These results confirm that it’s not necessarily the size of a genetic anomaly that confers risk, but its location – specifically in biochemical pathways involved in brain development and neural connections. Ultimately, it’s this kind of knowledge that will yield potential targets for new treatments,” explained Thomas, R. Insel, M.D., director of the NIH’s National Institute of Mental Health (NIMH), which funded one of the studies and fostered development of the Autism Sequencing Consortium, of which all three groups are members.

Multi-site research teams led by Mark Daly, Ph.D., of the Harvard/MIT Broad Institute, Cambridge, Mass., Matthew State, M.D., Ph.D., of Yale University, New Haven, Conn., and Evan Eichler, Ph.D., of the University of Washington, Seattle, report on their findings online April 4, 2012 in the journal Nature.

The study by Daly and colleagues was supported by NIMH – including funding under the American Recovery and Reinvestment Act. The State and Eichler studies were primarily supported by the Simons Foundation Autism Research Initiative. The studies also acknowledge the NIH’s National Human Genome Research Institute, National Heart Lung and Blood Institute, and National Institute on
Child Health and Human Development and other NIH components.

All three teams sequenced the protein coding parts of genes in parents and an affected child – mostly in families with only one member touched by autism. One study also included comparisons with healthy siblings. Although these protein-coding areas represent only about 1.5 percent of the genome, they harbor 85 percent of disease-causing mutations. This strategy optimized the odds for detecting the few spontaneous errors in genetic transmission that confer autism risk from the “background noise” generated by the many more benign mutations.

Like larger deletions and duplications of genetic material previously implicated in autism and schizophrenia, the tiny point mutations identified in the current studies are typically not inherited in the conventional sense – they are not part of parents’ DNA, but become part of the child’s DNA. Most people have many such glitches and suffer no ill effects from them. But evidence is building that such mutations can increase risk for autism if they occur in pathways that disrupt brain development.
State’s team found that 14 percent of people with autism studied had suspect mutations – five times the normal rate. Eichler and colleagues traced 39 percent of such mutations likely to confer risk to a biological pathway known to be important for communications in the brain.

Although Daly and colleagues found evidence for only a modest role of the chance mutations in autism, those pinpointed were biologically related to each other and to genes previously implicated in autism.

The Eichler team turned up clues to how environmental factors might influence genetics. The high turnover in a male’s sperm cells across the lifespan increases the chance for errors to occur in the genetic translation process. These can be passed-on to the offspring’s DNA, even though they are not present in the father’s DNA. This risk may worsen with aging. The researchers discovered a four-fold marked paternal bias in the origins of 51 spontaneous mutations in coding areas of genes that was positively correlated with increasing age of the father. So such spontaneous mutations could account for findings of an earlier study that found fathers of boys with autism were six times – and of girls 17 times – more likely to be in their 40’s than their 20’s.

“We now have a path forward to capture a great part of the genetic variability in autism – even to the point of being able to predict how many mutations in coding regions of a gene would be needed to account for illness,” said Thomas Lehner, Ph.D., chief of the NIMH Genomics Research Branch, which funded the Daly study and helped to create the Autism Sequencing Consortium. “These studies begin to tell a more comprehensive story about the molecular underpinnings of autism that integrates previously disparate pieces of evidence.”

“The Eichler team turned up clues to how environmental factors might influence genetics. The high turnover in a male’s sperm cells across the lifespan increases the chance for errors to occur in the genetic translation process. These can be passed-on to the offspring’s DNA, even though they are not present in the father’s DNA. This risk may worsen with aging.”

Of the papers, only one had the a form of the word “environment” in it (based on a very fast search):

Autism spectrum disorders (ASD) are believed to have genetic and environmental origins, yet in only a modest fraction of individuals can specific causes be identified1, 2. To identify further genetic risk factors, here we assess the role of de novo mutations in ASD by sequencing the exomes of ASD cases and their parents (n = 175 trios). Fewer than half of the cases (46.3%) carry a missense or nonsense de novo variant, and the overall rate of mutation is only modestly higher than the expected rate. In contrast, the proteins encoded by genes that harboured de novo missense or nonsense mutations showed a higher degree of connectivity among themselves and to previous ASD genes3 as indexed by protein-protein interaction screens. The small increase in the rate of de novo events, when taken together with the protein interaction results, are consistent with an important but limited role for de novo point mutations in ASD, similar to that documented for de novo copy number variants. Genetic models incorporating these data indicate that most of the observed de novo events are unconnected to ASD; those that do confer risk are distributed across many genes and are incompletely penetrant (that is, not necessarily sufficient for disease). Our results support polygenic models in which spontaneous coding mutations in any of a large number of genes increases risk by 5- to 20-fold. Despite the challenge posed by such models, results from de novo events and a large parallel case–control study provide strong evidence in favour of CHD8 and KATNAL2 as genuine autism risk factors.

Lessons can be learned from studying the severe genetic syndromes with an identified cause with high autism risk. Researchers can learn much about the origins of de novo sperm mutations from a study finding an aged paternal effect as seen in girls with autism. The comments section includes a full list ff references many of which include full text accessability. Visit the following web site for a further analysis and insight:

McD’s reference to darts reminded me of the NYT article written about these studies. Did anyone read this? If so, maybe you noticed a quote in the article from one of the lead scientists on the study. Commenting about their finding that 2 children out of ~150 had the same mutation in the exact same gene, Dr. State is quoted in article as saying:

“That is like throwing a dart at a dart board with 21,000 spots and hitting the same one twice…The chances that this gene is related to autism risk is something like 99.9999 percent.”

Wow, now that’s seriously bad use of probability statistics from a geneticist. See Michael Eisen’s commentary on this at his blog — a clear explanation about why this is a real Homer Simpson moment.

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Mr. Shatner, I see that you have been involved in a rather large tweet storm this weekend, focusing on your support for Autism Speaks. My guess is you would agree that 140 characters at a time is far too limiting to take on a complex discussion. Open letters such as this are as well, but […]

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What do these autism organizations have in common: Autism Science Foundation Autistic Self Advocacy Network Autism Society of America National Autistic Society Autistica The Marcus Autism Center The Thinking Person’s Guide to Autism I could list many more. Besides being autism organizations, they all have this in common: no mention of “Light It Up Blue” […]

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